The overall goal of this proposal is to develop a better understanding of the Ocular Mucosal Immune System (OMIS). The OMIS is the immune barrier that protects the eye from infection. This will be done in an experimental rabbit model whose ocular anatomy; immuno-histology and immune response to HSV infection mimics that of man. Our previous work has shown in rabbits mucosal ocular protection against HSV-1 was mediated by local mucosal, but not systemic immunization with HSV glycoprotein D (gD) and strong adjuvant. The mucosal protection in this model is due to cell-mediated immunity rather than secreted (slgA) or serum (IgG) antibodies. Using recently developed technologies, protective immunogenic HSV-1 gD peptide epitopes will be used to investigate the mechanism of ocular mucosal immunity and protection. These test peptides, formulated with novel, "safe" highly effective mucosal adjuvants will be administered topically to the eye to induce maximal local OMIS immunity. This research will be performed in these Specific Aims: Aim 1. Test the hypothesis that HSV-1 gD peptide epitopes found to stimulate the mouse mucosal immune system will also stimulate the rabbit OMIS and protect the eye against HSV challenge; Aim 2 -- Test the hypothesis that topical ocular delivery of the best protective gD peptides identified Aim 1 will activate Th1 immune responses in the OMIS. Aim 3A--Test the hypothesis that Nasal Associated Lymphoid Tissue (NALT) immunization is essential for OMIS responses and ocular protection and investigate whether the OMIS is part of the common mucosal immune system after topical delivery of gD peptides identified in Aim 1; and Aim 3B--Using high doses of our test antigens and the isolated NALT experimental system, we will test the hypothesis that NALT is necessary for induction of OMIS tolerance and, inversely, whether OMIS is involved in NALT tolerance. This research will provide important new information regarding the immunological composition and function of OMIS and explore means of inducing ocular mucosal immune protection and tolerance. It will test new technologies, new approaches in antigen presentation and mucosl adjuvants that could be stepping-stones to developing efficient ocular immunoprotective therapies. This addresses the NEI's Corneal Diseases Program objectives to "Further study of the mechanisms of mucosal immunity".